Department of Biomedical Engineering, Boston University, Boston, MA 02215.
Department of Chemistry, Boston University, Boston, MA 02215.
Proc Natl Acad Sci U S A. 2019 Jun 18;116(25):12183-12192. doi: 10.1073/pnas.1900355116. Epub 2019 Jun 3.
Arthrofibrosis is a prevalent condition affecting greater than 5% of the general population and leads to a painful decrease in joint range of motion (ROM) and loss of independence due to pathologic accumulation of periarticular scar tissue. Current treatment options are limited in effectiveness and do not address the underlying cause of the condition: accumulation of fibrotic collagenous tissue. Herein, the naturally occurring peptide hormone relaxin-2 is administered for the treatment of adhesive capsulitis (frozen shoulder) and to restore glenohumeral ROM in shoulder arthrofibrosis. Recombinant human relaxin-2 down-regulates type I collagen and α smooth muscle actin production and increases intracellular cAMP concentration in human fibroblast-like synoviocytes, consistent with a mechanism of extracellular matrix degradation and remodeling. Pharmacokinetic profiling of a bolus administration into the glenohumeral joint space reveals the brief systemic and intraarticular (IA) half-lives of relaxin-2: 0.96 h and 0.62 h, respectively. Furthermore, using an established, immobilization murine model of shoulder arthrofibrosis, multiple IA injections of human relaxin-2 significantly improve ROM, returning it to baseline measurements collected before limb immobilization. This is in contrast to single IA (sIA) or multiple i.v. (mIV) injections of relaxin-2 with which the ROM remains constrained. The histological hallmarks of contracture (e.g., fibrotic adhesions and reduced joint space) are absent in the animals treated with multiple IA injections of relaxin-2 compared with the untreated control and the sIA- and mIV-treated animals. As these findings show, local delivery of relaxin-2 is an innovative treatment of shoulder arthrofibrosis.
关节纤维性僵直是一种常见病症，影响超过 5%的普通人群，导致关节活动范围（ROM）疼痛性下降和丧失独立性，这是由于关节周围瘢痕组织病理性堆积所致。目前的治疗选择在效果上有限，并且不能解决病症的根本原因：纤维性胶原组织的积累。在此，天然存在的肽激素松弛素-2 被用于治疗粘连性肩关节囊炎（冻结肩）和恢复肩关节纤维性僵直的盂肱关节 ROM。重组人松弛素-2 下调 I 型胶原蛋白和α平滑肌肌动蛋白的产生，并增加人成纤维样滑膜细胞中的细胞内环腺苷酸（cAMP）浓度，与细胞外基质降解和重塑的机制一致。松弛素-2 关节内注射的药代动力学分析显示其在全身和关节内（IA）的半衰期短暂：分别为 0.96 h 和 0.62 h。此外，在已建立的、固定的肩部纤维性僵直的小鼠模型中，多次 IA 注射人松弛素-2 可显著改善 ROM，使其恢复到肢体固定前采集的基线测量值。这与单次 IA（sIA）或多次静脉内（mIV）注射松弛素-2 形成对比，后者的 ROM 仍然受到限制。与未治疗对照组和 sIA-和 mIV-治疗组相比，接受多次 IA 注射松弛素-2 的动物中不存在挛缩的组织学特征（例如，纤维性粘连和关节空间减少）。这些发现表明，局部给予松弛素-2 是治疗肩部纤维性僵直的一种创新方法。
